The goal of this Program is to establish a drug design cycle aimed at developing,testing and refining novel approaches to specific inhibitors of HIV-1 protease capable of limiting or eliminating drug resistance.Our contributionto this goal will be in the development and application of new chemical,biological and computationalapproaches that connect the structural and molecular basis of drug interaction to the clinical response. The program consists of four integrated Projects and two supporting Core facilities: 1) Computationalmodeling includingatomic detail co-evolution of HIV-proteasedrug resistance, modelingviral populationdynamics under drug selection pressure,and application of automated learningapproaches to inform and refine these models and relatedexperimental work in the other Projects.2) Design and development of next-generation inhibitors using rational and combinatorial synthetictechniques targeting both the protease and associated RNA structures. 3) Application of "Click Chemistry" in situ synthetic approaches for rapid development and evolution of inhibitors to drug resistant proteases;4) Investigationof the progression and limits of HIV protease variability by exploitingtissue-culturetime-course evaluation, phage display libraries and protease targeted RNA aptamer selection. 5) The Protein Expressionand Analysis Core will provide mutant and synthetic proteases,functional assays, chemical probes, and inhibitor analyses for the Program. 6) The Structure and Modeling Core will provide the necessary structural data and analysis to integrate new informationon protease mutants, and protease-inhibitorinteractions, as well as RNA aptamer-protein and RNA-inhibitorinteractions. The successful implementationand the application of the resulting knowledgeto therapeutic targets, would be a major contributionto the field of drug developmentand will be important in the design of new, more efficaciousAIDS therapeutics. ~